Multicomponent therapeutics for networked systems

Keith, Curtis T.; Borisy, Alexis A.; Stockwell, Brent R.

doi:10.1038/nrd1609

Cited by 700 publications

(561 citation statements)

References 52 publications

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“…Extensive research over the last half century has made clear that most chronic illnesses can only be cured by multitargeted, as opposed to mono-targeted, therapy [204][205][206] and that promiscuous targeting of a disease cell's multiple bypass mechanisms is a therapeutic virtue [207]. Consequently, agents that can modulate multiple cellular targets are now attractive objects of research.…”

Section: Discussionmentioning

confidence: 99%

Curcumin as “Curecumin”: From kitchen to clinic

Goel

Kunnumakkara

Aggarwal

2008

Biochemical Pharmacology

1,942

1,290

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Section: Discussionmentioning

confidence: 99%

Curcumin as “Curecumin”: From kitchen to clinic

Goel

Kunnumakkara

Aggarwal

2008

Biochemical Pharmacology

1,942

1,290

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“…To do so, we considered shapes corresponding to zero, linear and non-linear interactions between stresses, with the restrictions that the type of stress interaction is independent of the stress levels (that is, the niche boundary does not cross the additivity line), and that the sign of the curvature of the boundary is constant. An analogous approach is widely used in multicomponent drug therapeutics (Keith et al, 2005;Yeh et al, 2006), where it is known as isobolographic analysis (Gessner, 1995).…”

Section: Theorymentioning

confidence: 99%

Shape and evolution of the fundamental niche in marine Vibrio

et al. 2012

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Hutchinson’s fundamental niche, defined by the physical and biological environments in which an organism can thrive in the absence of inter-species interactions, is an important theoretical concept in ecology. However, little is known about the overlap between the fundamental niche and the set of conditions species inhabit in nature, and about natural variation in fundamental niche shape and its change as species adapt to their environment. Here, we develop a custom-made dual gradient apparatus to map a cross-section of the fundamental niche for several marine bacterial species within the genus Vibrio based on their temperature and salinity tolerance, and compare tolerance limits to the environment where these species commonly occur. We interpret these niche shapes in light of a conceptual model comprising five basic niche shapes. We find that the fundamental niche encompasses a much wider set of conditions than those strains typically inhabit, especially for salinity. Moreover, though the conditions that strains typically inhabit agree well with the strains’ temperature tolerance, they are negatively correlated with the strains’ salinity tolerance. Such relationships can arise when the physiological response to different stressors is coupled, and we present evidence for such a coupling between temperature and salinity tolerance. Finally, comparison with well-documented ecological range in V. vulnificus suggests that biotic interactions limit the occurrence of this species at low-temperature—high-salinity conditions. Our findings highlight the complex interplay between the ecological, physiological and evolutionary determinants of niche morphology, and caution against making inferences based on a single ecological factor.

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“…Although therapeutic synergy (TS) based on a TI has been explicitly ignored, for example, in the already mentioned review by Greco and colleagues (7), its importance has been acknowledged many times in the past (2,4,14,15). The concept therapeutic synergism was probably introduced for the first time in 1956 by Venditti and colleagues (16) and is simply defined to occur whenever a combination treatment provides improved therapy compared with the best-component single-drug therapy (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

“…This area has nonetheless attracted mounted interest in recent years due to vast unexplored prospects for future pharmacotherapeutic gains (1)(2)(3)(4)(5)(6). This development is also partly driven by a systems biology perspective acknowledging that many cellular processes are difficult to control using a single-drug compound, and partly by modern high-throughput laboratory equipment that make multicompound screening fast and cost effective.…”

Section: Introductionmentioning

confidence: 99%

A Pragmatic Definition of Therapeutic Synergy Suitable for Clinically Relevant In Vitro Multicompound Analyses

Kashif

Andersson

Åberg

et al. 2014

Molecular Cancer Therapeutics

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For decades, the standard procedure when screening for candidate anticancer drug combinations has been to search for synergy, defined as any positive deviation from trivial cases like when the drugs are regarded as diluted versions of each other (Loewe additivity), independent actions (Bliss independence), or no interaction terms in a response surface model (no interaction). Here, we show that this kind of conventional synergy analysis may be completely misleading when the goal is to detect if there is a promising in vitro therapeutic window. Motivated by this result, and the fact that a drug combination offering a promising therapeutic window seldom is interesting if one of its constituent drugs can provide the same window alone, the largely overlooked concept of therapeutic synergy (TS) is reintroduced. In vitro TS is said to occur when the largest therapeutic window obtained by the best drug combination cannot be achieved by any single drug within the concentration range studied. Using this definition of TS, we introduce a procedure that enables its use in modern massively parallel experiments supported by a statistical omnibus test for TS designed to avoid the multiple testing problem. Finally, we suggest how one may perform TS analysis, via computational predictions of the reference cell responses, when only the target cell responses are available. In conclusion, the conventional error-prone search for promising drug combinations may be improved by replacing conventional (toxicologyrooted) synergy analysis with an analysis focused on (clinically motivated) TS. Mol Cancer Ther; 13(7); 1964-76. Ó2014 AACR.

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Multicomponent therapeutics for networked systems

Cited by 700 publications

References 52 publications

Curcumin as “Curecumin”: From kitchen to clinic

Curcumin as “Curecumin”: From kitchen to clinic

Shape and evolution of the fundamental niche in marine Vibrio

A Pragmatic Definition of Therapeutic Synergy Suitable for Clinically Relevant In Vitro Multicompound Analyses

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